β cell replacement and regeneration therapies are promising approaches for the treatment of insulin-dependent type 1 (T1D) and type 2 diabetes (T2D) (Stewart, A. F. et al., Diabetes 64, 1872-1885 (2015); Wang, P. et al., Nature Reviews Endocrinology, 11, 201-212 (2015)). In rodents and humans, β cells are derived largely from two processes: neogenesis of β cells from ductal precursor cells, and replication of preexisting β cells (Dor, Y. et al., Nature 429, 41-46 (2004); Xu, X. et al., Cell, 132, 197-207 (2008); Garofano, A. et al.,FASEB J., 14, 2611-2617 (2000)). Neogenesis mostly occurs during fetal and neonatal life, whereas mitotic expansion of β cells in adults compensates for increased metabolic demands (Garofano, A. et al., FASEB J., 14, 2611-2617 (2000); Teta, M. et al., Diabetes 54, 2557-2567 (2005); Meier, J. J. et al., Diabetes 57, 1584-1594 (2008); Nir, T. et al., J Clin Invest, 117, 2553-2561 (2007); Lee, J. et al., eLife 2, e00940 (2013); Xiao, X. et al., J Clin Invest, 123, 2207-2217 (2013)). However, most adult pancreatic β cells are refractory to cell cycle entry and proliferation and remain in a state of senescence.
Of a dozen distinct TLR proteins, TLR2 and TLR4 are best known for their roles in the induction of innate and adaptive immune responses against all known pathogens such as viruses, fungi, bacteria, and protozoa (Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M. et al., Cell 86, 973-983 (1996); Medzhitov, R. et al., Nature 388, 394-397 (1997); Poltorak, A. et al., Science 282, 2085-2088 (1998)). Both gut microbiota derivatives such as LPS and LTA (Cani, P. D. et al., Diabetes 56, 1761-1772 (2007); Cani, P. D. et al., Diabetes 57, 1470-1481 (2008)) and fatty acids (Shi, H. et al., J Clin Invest 116, 3015-3025 (2006)) are likely endogenous ligands of TLR2 and TLR4. Despite intense research efforts from many laboratories, there is no overall consensus regarding the role of TLR2 and TLR4 in metabolism and in β cell function (Sun, S. et al., Annu Rev Nutr 32, 261-286 (2012); Donath, M. Y. et al., Cell Metab 17, 860-872 (2013)). Indeed, Tlr2 and Tlr4 single knockout mice exhibit mild and similar metabolic phenotypes, which were thought to be likely due to their redundant and compensatory functions (Lee, C. C. et al., Nat Rev Immunol, 12, 168-179 (2012)).